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Entheogen Receptor Activity
- Thread starter Fiashly
- Start date
Fiashly said:
Ray, Thomas S.
Psychedelics and the Human Receptorome
We currently understand the mental effects of psychedelics to be caused by agonism or partial agonism of 5-HT2A (and possibly 5-HT2C) receptors, and we understand that psychedelic drugs, especially phenylalkylamines, are fairly selective for these two receptors. This manuscript is a reference...
Although this report is interesting some of the conclusions drawn should be taken with a grain of salt (for example the list given in the conclusion b.w the diff drugs and the other (non-5-HT) important receptors) trying to relate the subjective effects of these drugs with these receptors would be a huge mistake. A role of ligand directed trafficking is also completely ignored with this logic. Not to mention the role of other untested receptor sites (Trace amine receptors ...).
However the raw ki values seem fine (NIMH PDSP is a respectable) and the study is a great source of data and it is definitely important and useful to researchers. It is a great reference just don't read to far into his conclusions.
Also the data manipulation given in the primary article is strange and non-classical and I have heard several pharmacologists have complained. It is a bit abstract and information may be lost in the "conversion". Its just confusing and unnecessary, Ki values are just fine (they are tangible and directly related) and are the standard in the field. I recommend getting the "Ki values" which are available and looking at them directly.
It should be clear that many of the binding results given for the individual receptors were performed using cloned receptors in cell lines and thus there relevance to in vivo is not known.
Many factors are involved that can not be accounted for in these cloned models. Don't get me wrong using cloned receptors in isolated cell systems is a useful in that you can be sure (with proper tests) that you are measuring affinity (Ki) for a single site however the relationship bw the results and what occurs in vivo is not known. Thus if one is aware of the limitations of these studies there are no problems.
Some of the limitations that arise from cloned receptor binding studies are:
1) The role of Post transcriptional modifications (In Vivo is likely very different)
2) Role of multiple receptors (If a drug binds to several sites than both the relative affinity and receptor concentrations of the sites are important factors)
3) In vivo Concentrations of respective receptors (Bmax values) (Even with the same affinity at two sites a higher concentration of one site MAY result in more significance of that site) Also binding at one site (with a given affinity) effects the available or free drug that can interact with other sites (thus concentrations and affinities at multiple receptor sites are important)
4) Most importantly however is the significance factor of a given receptor to the resulting effects of the drug (Only in vivo work can show this and furthermore with-out selective drugs even the conclusions from these studies should be viewed with caution. The notion of a truly selective drug is likely a false one. This goes for agonists and antagonists a like. Agonist directed trafficking is another major factor this is were different drugs can induce different effects on second messenger pathways via binding at the same receptor site.
Never the less if a drug has a high affinity for a given site it is likely that it will interact with that site in vivo the relative role of that receptor can in no way be inferred from binding data alone however.
However the raw ki values seem fine (NIMH PDSP is a respectable) and the study is a great source of data and it is definitely important and useful to researchers. It is a great reference just don't read to far into his conclusions.
Also the data manipulation given in the primary article is strange and non-classical and I have heard several pharmacologists have complained. It is a bit abstract and information may be lost in the "conversion". Its just confusing and unnecessary, Ki values are just fine (they are tangible and directly related) and are the standard in the field. I recommend getting the "Ki values" which are available and looking at them directly.
It should be clear that many of the binding results given for the individual receptors were performed using cloned receptors in cell lines and thus there relevance to in vivo is not known.
Many factors are involved that can not be accounted for in these cloned models. Don't get me wrong using cloned receptors in isolated cell systems is a useful in that you can be sure (with proper tests) that you are measuring affinity (Ki) for a single site however the relationship bw the results and what occurs in vivo is not known. Thus if one is aware of the limitations of these studies there are no problems.
Some of the limitations that arise from cloned receptor binding studies are:
1) The role of Post transcriptional modifications (In Vivo is likely very different)
2) Role of multiple receptors (If a drug binds to several sites than both the relative affinity and receptor concentrations of the sites are important factors)
3) In vivo Concentrations of respective receptors (Bmax values) (Even with the same affinity at two sites a higher concentration of one site MAY result in more significance of that site) Also binding at one site (with a given affinity) effects the available or free drug that can interact with other sites (thus concentrations and affinities at multiple receptor sites are important)
4) Most importantly however is the significance factor of a given receptor to the resulting effects of the drug (Only in vivo work can show this and furthermore with-out selective drugs even the conclusions from these studies should be viewed with caution. The notion of a truly selective drug is likely a false one. This goes for agonists and antagonists a like. Agonist directed trafficking is another major factor this is were different drugs can induce different effects on second messenger pathways via binding at the same receptor site.
Never the less if a drug has a high affinity for a given site it is likely that it will interact with that site in vivo the relative role of that receptor can in no way be inferred from binding data alone however.
